dimethyl 2-(methoxymethylidene)propanedioate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under the nitrogen gas atmosphere, a solution of 4-heptanone (5.0 mM, 35.75 mmol), n-butylamine (4.25 mL, 4.29 mmol), and three drops of concentrated hydrochloric acid was stirred for 18.5 hours at room temperature. After that, water was added and the mixture was extracted with ethyl acetate. After the organic layer had been washed with water and then dried with anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The obtained oily matter was dissolved in 2-methoxyethyl ether (40 mL), and heated and stirred with dimethyl methoxymethylenemalonate (5.66 g, 32.5 mmol) at 120° C. for 3 hours. After the solvent had been removed by distillation under reduced pressure, the residue was refined with silica gel (100 g) column chromatography (ethyl acetate-hexane of 1:1 in mixing ratio and then that of 2:1), and a ark reddish-brown oily substance was obtained. The substance was dissolved in THF (20 mL) without purification, and a 1M lithium hydroxide aqueous solution (15.18 mL) and water (4.82 mL) were added, and then the mixture was stirred for 2 hours at room temperature. After that, the mixture was diluted with water and washed with diethyl ether. After 2M hydrochloric acid had been added to the water layer to acidify it, the water layer was extracted with ethyl acetate. The organic layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and a pale yellow solid (AA03, 1.68 g, 18%) was obtained. the mixture was extracted with ethyl acetate After the organic layer had been washed with water dried with anhydrous sodium sulfate the solvent was removed by distillation under reduced pressure The obtained oily matter was dissolved in 2-methoxyethyl ether (40 mL) heated After the solvent had been removed by distillation under reduced pressure in mixing ratio that of 2:1), and a ark reddish-brown oily substance was obtained washed with diethyl ether After 2M hydrochloric acid had been added to the water layer the water layer was extracted with ethyl acetate The organic layer was washed with water dried with anhydrous sodium sulfate The solvent was removed by distillation under reduced pressure a pale yellow solid (AA03, 1.68 g, 18%) was obtained

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-7-pivalamidoquinazoline (10.5 g) and dimethyl methoxymethylenepropanedioate (10.9 g) in N,N-dimethylformamide (32 ml) was stirred at 100° C. for 1 hour and 25 minutes. After the reaction mixture was cooled to ambient temperature, water was added. The resulting solid was separated by filtration, washed with water and dried. The crystals were recrystallized from a mixture of ethyl acetate and ethanol to give crystalline dimethyl [[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (13.7 g). After the reaction mixture was cooled to ambient temperature The resulting solid was separated by filtration washed with water dried The crystals were recrystallized from a mixture of ethyl acetate and ethanol

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-6-(2,3-dimethylpentanamido)quinazoline (6.75 g) and dimethyl methoxymethylenepropanedioate (6.48 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 1 hour and cooled to ambient temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. There was obtained dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (6.58 g). A portion of the crude product was chromatographed on silica gel with chloroform and ethyl acetate (3:1) and recrystallized from ethyl acetate to give analytically pure dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (0.45 g). cooled to ambient temperature The resulting solid was separated by filtration washed with water dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-6-(3-cyclopentylpropionamido)quinazoline (7.05 g) and dimethyl methoxymethylenepropanedioate (6.48 g) in N,N-dimethylformamide (28 ml) was stirred at 100° C. for 1 hour and 10 minutes. After cooling to ambient temperature, water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. The crude crystals were dissolved in a mixture of chloroform and methanol, treated with activated charcoal, and evaporated under reduced pressure until crystallization began. After cooling, the resulting solid was collected, washed with methanol and with dichloromethane, and dried. There was obtained crystalline methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (2.16 g). The filtrate was evaporated under reduced pressure to give a residue which was chromatographed on silica gel with 1% methanoldichloromethane. The first fractions contained methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.9 g). The second fractions contained dimethyl [[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate (5.16 g). After cooling to ambient temperature The resulting solid was separated by filtration washed with water dried The crude crystals were dissolved in a mixture of chloroform and methanol treated with activated charcoal evaporated under reduced pressure until crystallization After cooling the resulting solid was collected washed with methanol and with dichloromethane dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-6-(2-methylpropionamido)quinazoline (6.2 g) and dimethyl methoxymethylenepropanedioate (7.01 g) in N,N-dimethylformamide (25 ml) was stirred at 100° C. for 1.5 hours and cooled to room temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water and dried to give dimethyl [[6-(2-methylpropionamido)-4-quinazolinylamino]methylene]propanedioate (8.9 g). Recrystallization from ethyl acetate gave pure crystals melting at 212°-214° C. cooled to room temperature The resulting solid was separated by filtration washed with water dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (5.58 g), dimethyl methoxymethylenepropanedioate (5.62 g) and N,N-dimethylformamide (22 ml) was stirred at 100° C. for 1.5 hours. After cooling to ambient temperature, water (90 ml) was added to the reaction mixture. The resulting solid was separated by filtration, washed with water and dried to give dimethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (4.85 g). After cooling to ambient temperature The resulting solid was separated by filtration washed with water dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-6-(3,3-dimethylbutyramido)quinazoline (8.5 g), dimethyl methoxymethylenepropanedioate (12.75 g) and N,N-dimethylformamide (34 g) was stirred for an hour at 100° C. After cooling to ambient temperature, to the resultant mixture was added water to give precipitates, which were separated by filtration, washed with water and dried to give crystalline dimethyl [{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate (10.9 g). to give precipitates which were separated by filtration washed with water dried

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-aminoquinazoline (7.27 g) and dimethyl methoxymethylenepropanedioate (9.6 g) in N,N-dimethylformamide (35 ml) was stirred for 2 hours at 150° C. The reaction mixture was cooled to ambient temperature and poured into ice-water to give crystals, which were separated by filtration, washed with water and dried to ambient temperature to give a mixture (13.3 g) of dimethyl [(4-quinazolinylamino)methylene]propanedioate and methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate. The reaction mixture was cooled to ambient temperature to give crystals, which were separated by filtration washed with water dried to ambient temperature

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 12.3 g (0.1 Mol) of p-Anisidine in 50 ml of ethanol, a solution of 17.4 g (0.1 Mol) of Dimethyl methoxymethylenemalonate in 70 ml of ethanol was added dropwise with stirring at room temperature. After an additional hour of stirring at that temperature, the reaction mixture was cooled with an ice bath and the product cristallised spontanously. The crude solid material was isolated by filtration and washed with ethanol and gave 12.9 g of the title product which is a white solid melting at 89-91° C., UV 328 nm (E=899). After an additional hour of stirring at that temperature the reaction mixture was cooled with an ice bath The crude solid material was isolated by filtration washed with ethanol